Thyroid hormone plays critical roles in development and differentiation, as well as regulating the metabolic rate in the adult. The four subtypes of the thyroid hormone receptor (TR), alpha1, alpha2, beta1 and beta2 are expressed in different ratios in different tissues. Therefore, subtype-selective TR agonists may be used to simulate the desired effects of thyroid hormone in target tissues, while avoiding undesirable side-effects. We have developed a potent, halogen-free thyromimetic, dubbed GC-1, which shows a modest preference in binding to and activating TR-beta. Additionally, no high affinity antagonist of TR has been reportd. However, the structures of antagonists for related nuclear receptors suggest strategies for its design. These antagonists have structures which resemble corresponding agonists but contain a large hydrophobic appendage which prevent the ligand-receptor complex from adopting a conformation associated with the activation of transcription. Our current goals are: 1) to elucidate the ligand-receptor molecular recognition features which differ between TR-alpha and beta and to use this knowledge to develop TR-alpha-selective ligands, as well as those with enhanced TR-beta selectivity; and 2) search for TR antagonists with a series of GC-1 analogues that bear large hydrophobic appendages at the middle of the molecule.